Dihydro-1,3,5-triazines have been shown to be useful in the treatment of pathologies associated with insulin resistance, in particular type II diabetes (see WO2001/055122).
It is known that the biological activity of enantiomers of racemic compounds can differ considerably depending on the two enantiomers. Consequently, there is often one enantiomer that has more pronounced activity, making it more advantageous as an active principle in a medicament.
The use of this enantiomer instead of the racemate is advantageous. Specifically, the higher activity of the identified enantiomer makes it possible to reduce the dosage of active principle in the medicament. The lower dosage then allows a reduction of the adverse side effects. It is thus desirable for an active principle to be composed of only the pure enantiomer that has the largest desired biological effects.
Numerous methods exist for separating a racemic mixture into its two pure enantiomers. For further information in this respect, reference is made especially to the book “Chirotechnology” by R. A. Sheldon (1993) published by Dekker.
Examples of such processes that may be mentioned include:                separation based on a physical property difference        separation based on the use of biotechnological methods (whole cells, enzymes, etc.)        separation based on the use of chromatographic methods        separation based on the formation of diastereoisomers (salts, addition of a chiral centre).        
Several processes have been described to date allowing separation of both enantiomers of dihydro-1,3,5-triazines. These enantiomers have been for instance separated by formation of diastereoisomeric salts (WO2004/089917), by particle size-controlled crystallization (PCT/EP2009/059769), and by preferential crystallization (PCT/EP2010/054037).
The previously described process involving formation of diastereoisomeric salts is specific of certain chiral reagents. In particular, the process requires the desired diastereoisomeric salt to selectively crystallize to be recovered from the medium, and that is not the case with all chiral reagents. The most efficient chiral reagents to be used in this process, such as di-O,O′-p-toluoyl-L-tartaric acid, are quite expensive and not as easily available as tartaric acid. Further, the starting material for this process is the triazine derivative under its free base form, and as usual preparation routes lead to the hydrochloride salt of the triazine derivatives, this process necessarily implies a step of re-formation of the free triazine derivative from the corresponding hydrochloride salt.
In this context, the Applicant surprisingly discovered a new process for separating enantiomers of the triazine derivatives by formation of diastereoisomeric salts, involving tartaric acid as chiral reagent. This process affords the separation of enantiomers in higher yield, with lower impurities and with lower expenses than the previously described process. The main drawbacks of the prior art process are actually overcome by the possibility to proceed directly from a salt of the triazine and by the unexpected crystallization of the desired dihydro-1,3,5-triazine salt.